Cytokines such as TNFs, interleukins, and interferons are intercellular signaling substances which play an important role in a biological defense system such as an immune system, a blood system, or an inflammatory response.
Immune response is triggered through recognition of a substance stimulating cytokine production by a pattern recognition receptor (PRR) (e.g., toll-like receptor (TLR)) whose expression is observed in host immunocytes, particularly in, for example, macrophages or dendritic cells. Immune response is regulated through direct or indirect interaction between immunocompetent cells (e.g., macrophages, dendritic cells, or lymphocytes).
Generally, living organisms cope with, for example, bacterial or viral infection, tumor, or cytotoxicity through activation of immune response. As has been shown, induction of excessive immune response may cause an allergic disease such as atopic dermatitis, bronchial asthma, allergic rhinitis, allergic conjunctivitis, or food allergy, or an autoimmune disease such as systemic lupus erythematosus (SLE) or chronic rheumatoid arthritis. Therefore, it is important that cytokine production in a living organism can be regulated so as to achieve a more desirable state.
In recent years, attempts have been made to use a microorganism or a microorganism-derived component as a cytokine-production-regulating substance; i.e., a biological response modifier (BRM). Hitherto, there have been reported, for example, the cytokine production promoting effect of a polysaccharide-glycan complex derived from a Gram-positive bacterium (Patent Document 1), the interleukin (IL)-6 production inhibitory effect of a polysaccharide fraction derived from a bacterium belonging to the genus Lactobacillus or cells thereof (Patent Document 2), the IL-15 production promoting effect of lactobacillus cells (Patent Document 3), the IL-12 production promoting effect of cells of Lactobacillus casei, etc. (Patent Document 4), the macrophage activation effect of a polysaccharide-peptidoglycan complex derived from a bacterium belonging to the genus Lactobacillus (Patent Document 5), and the tumor cytotoxic factor inducing effect of a polysaccharide-peptidoglycan complex derived from a bacterium belonging to the genus Lactobacillus (Patent Document 6).
As has been shown, in the cytokine production regulatory effect of Lactobacillus casei YIT 9018 (FERM BP-665) or Lactobacillus casei YIT 9029 (FERM BP-1366), a polysaccharide-peptidoglycan complex (PS-PG) (i.e., a cell wall component) serves as an active center (Patent Document 2). However, elucidation at the genetic level has not yet been accomplished.
As has been reported, attempts have been made to modify the cytokine production regulatory activity of a microorganism at the genetic level by introducing the listeriolysin O gene, which is a listerial hemolysin, into Lactobacillus casei ATCC 393 (Patent Document 7). However, this modification causes problems in terms of safety or effectiveness and thus has not yet been put into practice. There has also been reported a gene involved in biosynthesis of an exopolysaccharide which is extracellularly produced by lactic acid bacterium (Patent Document 8). However, this exopolysaccharide is provided for the purpose of thickening foods or making foods creamy, and the exopolysaccharide has a structure different from that of a polysaccharide contained in the aforementioned PS-PG.    Patent Document 1: JP-A-1996-92112    Patent Document 2: JP-A-2003-73286    Patent Document 3: JP-A-2002-241292    Patent Document 4: JP-A-1998-139674    Patent Document 5: JP-B-1994-99314    Patent Document 6: JP-A-1988-196521    Patent Document 7: JP-A-2003-63991    Patent Document 8: JP-A-1997-269